Sugars appended to pharmaceutically important natural products are known to influence drug solubility, pharmacology, target recognition, toxicity and mechanism of action (Thorson, J. S.; Vogt, T. Carbohydrate-Based Drug Discovery 2003, 685. Wong C H. (Ed): Weinheim:Wiley-VCH). However, studies designed to systematically understand and exploit the role of carbohydrates in drug discovery are often limited by the availability of practical synthetic tools (Griffith, B. R., et al., Curr. Opin. Biotech. 2005, 16, 622). For instance, two complementary strategies that allow for the rapid glycosylation of natural product scaffolds have been reported. The first (chemoenzymatic glycorandomization) utilizes a set of flexible enzymes (an anomeric kinase, sugar-1-phosphate nucleotidylyltransferase and natural product glycosyltransferase), (Zhang, C. et al., Science 2006, 313, 1291) while the second (neoglycorandomization) employs a single reaction between a free reducing sugar and a methoxyamine-appended aglycon (Langenhan, J. M. et al., Proc. Natl. Acad. Sci. U.S.A. 2005, 102, 12305). While both methods have been successful in preparing a glycorandomized library and identifying compounds with notable activities (Fu, X., et al., Nat. Biotech. 2003, 21, 1467), applications of glycorandomization to date have been restricted to the natural positions of O-glycosylation within natural products.
Glycosylation of natural compounds alters their bioavailability and pharmacokinetics (Koyama, H. et al., Biopharm Drug Dispos. 1997 December; 18(9):791-801). Further, other studies have shown that glycosylation can be exploited to design recombinant drugs which optimize pharmacokinetics (Klgelberg, H., Glycobiology, 2006 Sep. 25). However, in these cases the glycosylated bioactive compounds had naturally occurring glycosylated derivatives.
Colchicine is one bioactive compound that does not have naturally occurring glycosylated derivatives. Colchicine is an alkaloid known as a treatment for gout, Bechet's disease and Mediterranean fever as well as for its cathartic and emetic effects. Colchicine is also thought to have efficacy as a treatment for cancer. Unfortunately, colchicine's effectiveness as a therapeutic is limited by its toxicity as high doses can result in death from respiratory failure.
In the search for a wider spectrum of antibiotics and therapeutics, the present invention provides a method to synthesize and identify glycosylated derivatives or analogs of naturally occurring bioactive compounds there are not normally glycosylated in nature. Thus, the bioactivity and pharmacokinetics of such compounds could be altered to provide new classes of compounds with hitherto unidentified actions and/or actions that are hybrid between the non-glycosylated base and the carbohydrate moiety that is conjugated thereto.